EP0002742B1 - Dérivés de stilbène, leur préparation et médicaments contenant ces dérivés de stilbène - Google Patents
Dérivés de stilbène, leur préparation et médicaments contenant ces dérivés de stilbène Download PDFInfo
- Publication number
- EP0002742B1 EP0002742B1 EP78101700A EP78101700A EP0002742B1 EP 0002742 B1 EP0002742 B1 EP 0002742B1 EP 78101700 A EP78101700 A EP 78101700A EP 78101700 A EP78101700 A EP 78101700A EP 0002742 B1 EP0002742 B1 EP 0002742B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tetramethyl
- tetrahydro
- formula
- naphthyl
- propenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000003814 drug Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 11
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical class C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 title description 4
- 229940079593 drug Drugs 0.000 title description 2
- -1 hydroxy-lower-alkyl Chemical group 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- FOIVPCKZDPCJJY-JQIJEIRASA-N arotinoid acid Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C1=CC=C(C(O)=O)C=C1 FOIVPCKZDPCJJY-JQIJEIRASA-N 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 3
- ZWGKNXJBFOWLFM-OBGWFSINSA-N 6-[(e)-1-[4-(methoxymethyl)phenyl]prop-1-en-2-yl]-1,1,4,4-tetramethyl-2,3-dihydronaphthalene Chemical compound C1=CC(COC)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 ZWGKNXJBFOWLFM-OBGWFSINSA-N 0.000 claims description 3
- 229940007550 benzyl acetate Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- LXNWFBFISUENQC-OBGWFSINSA-N ethyl 4-[(e)-2-(3-methoxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1\C=C(/C)C1=CC(C(CCC2(C)C)(C)C)=C2C=C1OC LXNWFBFISUENQC-OBGWFSINSA-N 0.000 claims 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 120
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- XBCVARFSRWLPOC-UHFFFAOYSA-N 1-(1,1,3,3-tetramethyl-2h-inden-5-yl)ethanone Chemical compound CC(=O)C1=CC=C2C(C)(C)CC(C)(C)C2=C1 XBCVARFSRWLPOC-UHFFFAOYSA-N 0.000 description 22
- 239000000155 melt Substances 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- WINIVVAOBFDASO-SAPNQHFASA-N 4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzaldehyde Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C1=CC=C(C=O)C=C1 WINIVVAOBFDASO-SAPNQHFASA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 9
- 239000003480 eluent Substances 0.000 description 8
- 239000012259 ether extract Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- GWODBVDCNSWNFM-SAPNQHFASA-N [4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]phenyl]methanol Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C1=CC=C(CO)C=C1 GWODBVDCNSWNFM-SAPNQHFASA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 230000000699 topical effect Effects 0.000 description 7
- NLIUDONFMFYFRU-UHFFFAOYSA-M triphenyl-[1-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethyl]phosphanium;bromide Chemical compound [Br-].C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(C)[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NLIUDONFMFYFRU-UHFFFAOYSA-M 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- BHYVHYPBRYOMGC-UHFFFAOYSA-N ethyl 4-formylbenzoate Chemical compound CCOC(=O)C1=CC=C(C=O)C=C1 BHYVHYPBRYOMGC-UHFFFAOYSA-N 0.000 description 6
- 229910052987 metal hydride Inorganic materials 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 150000004681 metal hydrides Chemical class 0.000 description 5
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 5
- IWIWGFMIKABCFO-UHFFFAOYSA-N 1,1,3,3-tetramethyl-2h-indene Chemical compound C1=CC=C2C(C)(C)CC(C)(C)C2=C1 IWIWGFMIKABCFO-UHFFFAOYSA-N 0.000 description 4
- PXSMPYKGNAUXBM-BMRADRMJSA-N 1-[4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 PXSMPYKGNAUXBM-BMRADRMJSA-N 0.000 description 4
- KTFKRVMXIVSARW-UHFFFAOYSA-N 4-acetylbenzaldehyde Chemical compound CC(=O)C1=CC=C(C=O)C=C1 KTFKRVMXIVSARW-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- NULUAKSYPPSJCO-FBMGVBCBSA-N ethyl 4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 NULUAKSYPPSJCO-FBMGVBCBSA-N 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 150000004714 phosphonium salts Chemical class 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- FYPPFNIHEQRSSA-UHFFFAOYSA-M triphenyl-[1-(1,1,3,3-tetramethyl-2h-inden-5-yl)ethyl]phosphanium;bromide Chemical compound [Br-].C=1C=C(C(CC2(C)C)(C)C)C2=CC=1C(C)[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 FYPPFNIHEQRSSA-UHFFFAOYSA-M 0.000 description 4
- CPGWXXQRRMYQHF-UHFFFAOYSA-N 1-(1,1,3,3-tetramethyl-6-nitro-2h-inden-5-yl)ethanone Chemical compound C1=C([N+]([O-])=O)C(C(=O)C)=CC2=C1C(C)(C)CC2(C)C CPGWXXQRRMYQHF-UHFFFAOYSA-N 0.000 description 3
- KTDVIXSXSBABNJ-UHFFFAOYSA-N 1-(6-chloro-1,1,3,3-tetramethyl-2h-inden-5-yl)ethanone Chemical compound C1=C(Cl)C(C(=O)C)=CC2=C1C(C)(C)CC2(C)C KTDVIXSXSBABNJ-UHFFFAOYSA-N 0.000 description 3
- KDVZUARNRGKIKF-UHFFFAOYSA-N 1-(7-methoxy-1,1,3,3-tetramethyl-2h-inden-5-yl)ethanone Chemical compound COC1=CC(C(C)=O)=CC2=C1C(C)(C)CC2(C)C KDVZUARNRGKIKF-UHFFFAOYSA-N 0.000 description 3
- ZUGRLOSFUMNNDN-UHFFFAOYSA-M 1-(7-methoxy-1,1,3,3-tetramethyl-2h-inden-5-yl)ethyl-triphenylphosphanium;bromide Chemical compound [Br-].C=1C(C(CC2(C)C)(C)C)=C2C(OC)=CC=1C(C)[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZUGRLOSFUMNNDN-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)(*C1(*)*)C2=C1C(*)=C(*)C(*)C2 Chemical compound CC(C)(*C1(*)*)C2=C1C(*)=C(*)C(*)C2 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- WTWBUQJHJGUZCY-UHFFFAOYSA-N cuminaldehyde Chemical compound CC(C)C1=CC=C(C=O)C=C1 WTWBUQJHJGUZCY-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- PEQVEWGYWQOOPU-UHFFFAOYSA-M triphenyl-[(1,1,3,3-tetramethyl-2h-inden-5-yl)methyl]phosphanium;chloride Chemical compound [Cl-].C=1C=C2C(C)(C)CC(C)(C)C2=CC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 PEQVEWGYWQOOPU-UHFFFAOYSA-M 0.000 description 3
- SVPDQMCYGWKADZ-UHFFFAOYSA-M triphenyl-[1-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)propyl]phosphanium;bromide Chemical compound [Br-].C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(CC)[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 SVPDQMCYGWKADZ-UHFFFAOYSA-M 0.000 description 3
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- KNXSPRQSYPCLHC-OBGWFSINSA-N ethyl 2-methyl-4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoate Chemical compound C1=C(C)C(C(=O)OCC)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 KNXSPRQSYPCLHC-OBGWFSINSA-N 0.000 description 1
- UMJKMAVWRRMXHP-UHFFFAOYSA-N ethyl 4-formyl-3-methylbenzoate Chemical compound CCOC(=O)C1=CC=C(C=O)C(C)=C1 UMJKMAVWRRMXHP-UHFFFAOYSA-N 0.000 description 1
- JHYNXXDQQHTCHJ-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 JHYNXXDQQHTCHJ-UHFFFAOYSA-M 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N hydroxymethylethylene Natural products OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- 201000006122 hypervitaminosis A Diseases 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000002468 indanes Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- BGVKRLLRRWJDMN-CZIZESTLSA-N morpholin-4-yl-[4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]phenyl]methanone Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C(C=C1)=CC=C1C(=O)N1CCOCC1 BGVKRLLRRWJDMN-CZIZESTLSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- ZKULOXDHSGQEQE-CZIZESTLSA-N n,n-diethyl-4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 ZKULOXDHSGQEQE-CZIZESTLSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- ORVJTFDUQVNOBD-FBMGVBCBSA-N n-ethyl-4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzamide Chemical compound C1=CC(C(=O)NCC)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 ORVJTFDUQVNOBD-FBMGVBCBSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- YYFIGOPUHPDIBO-UHFFFAOYSA-N propanoic acid;hydrochloride Chemical compound Cl.CCC(O)=O YYFIGOPUHPDIBO-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/34—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen reacting phosphines with aldehydes or ketones, e.g. Wittig reaction
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/47—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing ten carbon atoms
- C07C13/48—Completely or partially hydrogenated naphthalenes
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C07C33/34—Monohydroxylic alcohols containing six-membered aromatic rings and other rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/164—Unsaturated ethers containing six-membered aromatic rings
- C07C43/168—Unsaturated ethers containing six-membered aromatic rings containing six-membered aromatic rings and other rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/548—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings having unsaturation outside the six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/782—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic
- C07C49/792—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic containing rings other than six-membered aromatic rings
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
- C07C49/798—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring containing rings other than six-membered aromatic rings
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/66—Polycyclic acids with unsaturation outside the aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/12—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals containing only hydrogen and carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/12—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5456—Arylalkanephosphonium compounds
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12C—BEER; PREPARATION OF BEER BY FERMENTATION; PREPARATION OF MALT FOR MAKING BEER; PREPARATION OF HOPS FOR MAKING BEER
- C12C11/00—Fermentation processes for beer
- C12C11/02—Pitching yeast
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- FR-PS 1 576 018 mentions stilbene and unsaturated naphthalene derivatives which e.g. can be substituted by a phenyl radical. A pharmacological effect of these compounds is not known, rather they are described as intermediates in the production of optical brighteners.
- GB-PS 1 465 661 stilbene acetic acid derivatives are described which are anti-inflammatory and analgesic.
- the invention further relates to medicaments based on compounds of the formula I or their salts and a process for the preparation of the compound I.
- lower used here denotes groups with up to 6 carbon atoms.
- Alkyl and alkoxy groups can be branched or unbranched, for example methyl, ethyl, isopropyl or 2-methylpropyl or methoxy, ethoxy or isopropoxy.
- Alkanoyl groups derive e.g. from acetic, propionic or pivalic acid or also from the higher carboxylic acids with up to 20 carbon atoms, e.g. on palmitic or stearic acid.
- a preferred aryl radical is phenyl.
- Examples of substituted aryl radicals are hydroxyl, nitro or halophenyl.
- a preferred aralkyl radical is benzyl.
- heterocyclic radicals -N are 5- or 6-membered nitrogen-containing heterocyclic radicals which can contain a further O, N or S atom, for example piperidino, piperazino, morpholino, thiamorpholino and pyrrolidino.
- ketals are di-lower alkyl ketals and lower alkylene ketals.
- the oxazolinyl radical can be substituted by one or two lower alkyl groups.
- halogen atoms chlorine and bromine are preferred.
- R 1 , R 2 , R 5 , R e , R 8 and R 9 are hydrogen and R 3 , R 4 and R 7 are methyl.
- the compounds of the formula I are obtained by adding a compound of the general formula with a compound of the general formula in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 and n have the above meaning, and either A is a triarylphosphoniumalkyl group of the formula i R-CH-P [Q ] 3 ⁇ represents Y ⁇ , wherein R denotes hydrogen, methyl or ethyl, Q denotes an aryl residue and Y denotes the anion of an organic or inorganic acid, and B is formyl; or A is formyl, acetyl or propionyl, and B is a dialkoxyphosphinylalkyl group of the formula represents, wherein Z denotes a lower alkoxy radical; converts to a compound of general formula I, and if desired modifies the radical R 10 functionally.
- the aryl groups denoted by Q in the triarylphosphonium groups mentioned generally comprise all known aryl radicals, but in particular mononuclear radicals, such as phenyl or lower alkyl, or lower alkoxy-substituted phenyl, such as tolyl, xylyl, mesityl or p-methoxyphenyl.
- the inorganic acid anions Y the chlorine and bromine ion or the hydrosulfate ion is preferred, of the organic acid anions the tosyloxy ion is preferred.
- the in the dialkoxyphosphinylalkyl group of the formula Alkoxy radicals denoted by Z are primarily lower alkoxy radicals having 1-6 carbon atoms, such as methoxy or ethoxy.
- Suitable acylating agents are formaldehyde / hydrochloric acid acetyl and propionyl halides e.g. Acetyl and propionyl chloride.
- the Lewis acids the halides of aluminum, such as aluminum trichloride, are preferred.
- the reaction is conveniently carried out in a solvent, such as nitrobenzene, or in a chlorinated hydrocarbon, such as methylene chloride.
- the reaction temperature is primarily 0 to about + 5 ° C.
- the resulting oxo compound of the formula II in which R 1 and R 2 are hydrogen is, according to the invention, condensed with a phosphonate of the formula III in which B represents a dialkoxyphosphinylmethyl group to give compounds of the formula I in which R 1 and R 2 are hydrogen.
- Oxo compounds and phosphonium salts of the formula II, in which the substituents R 1 and R 2 are alkoxy or halogen, can be prepared, for example, by treating the corresponding phenol in a manner known per se by treatment with an alkylating agent, for example by reaction with a lower one Converted alkyl halide or with a lower alkanol in the presence of an acidic agent into the corresponding alkoxy derivative of formula II.
- the diazonium salt prepared from the amine is treated with a copper (1) halide under heat, the corresponding halogen derivative of the oxo compound of the formula II is obtained.
- the halogen derivative obtained again with nitrating acid, it is possible in the m-position to formyl , Acetyl or propionyl group to introduce a nitro group which can also be converted to hydroxy or halogen as described above.
- the hydroxyl group into alkoxy, the same or mixed-substituted derivatives of the starting ketones of the formula II are obtained, as desired.
- a halogen atom in the aromatic nucleus can be removed again by reduction in a manner known per se.
- B For myl means can be prepared from phenyl derivatives which are nitro-substituted in the 1-position, as described in Chem. reports 102 (1969) on pages 2502-2507. They are also accessible by reducing the corresponding p-carboxy-substituted phenyl derivatives.
- the reduction of the carboxyl to formyl group can be carried out, for example, with diisobutyl aluminum hydride.
- the condensation components of formula 111 in which B represents a dialkoxyphosphinylmethyl group, can be prepared from the above compounds of formula 111, in which B means formyl in such a way that the formyl group can be obtained using a metal hydride, e.g. converted with the help of sodium borohydride into the hydroxymethyl group, this using one of the usual halogenating agents, e.g. halogenated with phosphorus trichloride and the halogen derivative obtained is reacted with a trialkyl phosphite, in particular with triethyl phosphite, to give the desired phosphonate of the formula III.
- B means formyl in such a way that the formyl group can be obtained using a metal hydride, e.g. converted with the help of sodium borohydride into the hydroxymethyl group, this using one of the usual halogenating agents, e.g. halogenated with phosphorus trichloride and the hal
- the condensation component of the formula III in which B is formyl or a dialkoxyphosphinylmethyl group can also be obtained by halogenating the corresponding phenyl derivative which is methyl-substituted in the 1-position and either reacting the halogenomethyl derivative obtained with a trialkyl phosphite or hydrolyzing it to the hydroxymethyl derivative and treating it with an oxidizing agent, e.g. oxidized with manganese dioxide.
- an oxidizing agent e.g. oxidized with manganese dioxide.
- a carboxylic acid ester of formula I can e.g. B. be converted directly into the corresponding amide by treatment with lithium amide.
- the lithium amide is advantageously reacted with the ester in question at room temperature.
- An alcohol of the formula I can also be esterified by treatment with an alkanoyl halide or anhydride, advantageously in the presence of a base, for example in the presence of pyridine or triethylamine, in a temperature range between room temperature and the boiling point of the reaction mixture.
- the carboxylic acids of the formula I form salts with bases, in particular with the alkali metal hydroxides, preferably with sodium or potassium hydroxide.
- the majority of the compounds of formula 1 are in the trans form. If necessary, cis fractions can be separated in a manner known per se, if desired, or isomerized to the trans compounds.
- the process products of the formula I are pharmacodynamically valuable compounds. They can be used for topical and systemic therapy of benign and malignant neoplasms, of premalignant lesions, and also for systemic and topical prophylaxis of the affection mentioned.
- the new compounds are distinguished from known retinoids in that they are active in extremely small amounts.
- the compounds of the formula I and their salts can also be used for the oral treatment of rheumatic diseases, in particular those of an inflammatory and degenerative nature which affect joints, muscles, tendons and other parts of the musculoskeletal system.
- rheumatic diseases in particular those of an inflammatory and degenerative nature which affect joints, muscles, tendons and other parts of the musculoskeletal system.
- diseases are primarily chronic polyarthritis, spondylarthritis ankylopoetica Bechterew and Arthropathia psoriatica.
- the compounds according to the invention are administered orally, expediently in an adult dosage of about 0.01-1 mg per day, preferably 0.05-0.5 mg per day.
- a possible overdose can manifest itself in the form of Vit-A hypervitaminosis and is easily recognizable by its symptoms (skin flaking, hair loss).
- the dose can be administered as a single dose or in several divided doses.
- the compounds of the formula can therefore be used as medicines, e.g. B. in the form of pharmaceutical preparations.
- the preparations for systemic use can e.g. can be prepared by adding a compound of the formula I as an active ingredient to non-toxic, inert solid or liquid carriers which are customary in such preparations.
- agents can be administered enterally, parenterally or topically.
- enteral application z.
- the dosages in which the process products are administered can vary depending on the type of application and route of use and on the needs of the patients.
- the process products can be administered in amounts of about 0.01 to 5 mg daily in one or more doses.
- a preferred dosage form are capsules with a content of about 0.1 to 1.0 mg of active ingredient.
- the above-mentioned carriers and diluents can be made from organic or inorganic substances, e.g. B. from water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and. Like exist. The prerequisite is that all auxiliary substances used in the manufacture of the preparations are non-toxic.
- ointments or creams are expediently suitable for topical use.
- triphenylphosphine 26.3 g triphenylphosphine are dissolved in 120 ml xylene. 30.9 g of 5- (1-bromoethyl) -1,1,3,3-tetramethyl-indane, dissolved in 60 ml of xylene, are added to the solution. The mixture is heated to 100 ° C. with stirring and left at this temperature for 12 hours. The resulting thick, oily, crystallizing after seeding, 1- (1,1,3,3-tetramethyl-5-indanyl) ethyl triphenylphosphonium bromide melts after recrystallization from methylene chloride / toluene at 151-156 ° C (crystals contain 0, 3 equivalents of toluene).
- the 3-methyl-4-ethoxycarbonyl-benzaldehyde used as the condensation component can be prepared starting from 4-nitro-3-methyl-benzoic acid in an analogous manner to that for the preparation of the 2-methyl-4-ethoxycarbonyl-benzaldehyde by Huneck et al . in Chem. Ber. 102: 2502-2507 (1969).
- the organic extract is washed with a saline solution, dried over sodium sulfate and freed from the solvent under reduced pressure.
- the residue is purified by adsorption on silica gel [eluent hexane / acetone 19: 1].
- the (6-chloro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts at 69-71 ° C. after recrystallization from hexane / ether.
- the organic phase is washed with a saline solution, dried over sodium sulfate and freed from the solvent under reduced pressure.
- the residue is purified by adsorption on silica gel [eluent hexane / ether 19: 1].
- the (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts at 78-80 ° C. after recrystallization from hexane / ether.
- the white suspension is stirred for 2% hours at room temperature, diluted with ethyl acetate, washed three times with water, dried over sodium sulfate and concentrated under reduced pressure.
- the white crystalline residue is suspended in 20 ml of ether and 6 g of thionyl chloride are added dropwise at 0 ° C.
- the white suspension is stirred for 30 minutes at room temperature and then carefully mixed with a saturated sodium carbonate solution until the pH is - 9.
- the now clear solution is diluted with ether.
- the ether phase is washed three times with a saturated saline solution, dried over sodium sulfate and evaporated under reduced pressure.
- the ether extract is washed twice with a saturated saline solution, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure.
- the oily residue is purified by absorption on silica gel (eluent: hexane / ether 9: 1).
- Capsules for oral administration can have the following composition:
- An ointment can have the following composition:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (15)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU78751 | 1977-12-22 | ||
LU78751 | 1977-12-22 | ||
CH1159078 | 1978-11-10 | ||
CH11590/78 | 1978-11-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0002742A1 EP0002742A1 (fr) | 1979-07-11 |
EP0002742B1 true EP0002742B1 (fr) | 1982-04-14 |
Family
ID=25708596
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78101700A Expired EP0002742B1 (fr) | 1977-12-22 | 1978-12-15 | Dérivés de stilbène, leur préparation et médicaments contenant ces dérivés de stilbène |
Country Status (32)
Country | Link |
---|---|
EP (1) | EP0002742B1 (fr) |
JP (1) | JPS54109955A (fr) |
AR (1) | AR224357A1 (fr) |
AT (1) | AT361459B (fr) |
AU (1) | AU525419B2 (fr) |
BR (1) | BR7808470A (fr) |
CA (1) | CA1123839A (fr) |
CS (1) | CS208158B2 (fr) |
CU (1) | CU35002A (fr) |
CY (1) | CY1277A (fr) |
DE (2) | DE2861748D1 (fr) |
DK (1) | DK159967C (fr) |
DO (1) | DOP1978002760A (fr) |
ES (1) | ES476224A1 (fr) |
FI (1) | FI68804C (fr) |
FR (1) | FR2422620A1 (fr) |
GB (1) | GB2010836B (fr) |
GR (1) | GR71656B (fr) |
HK (1) | HK30185A (fr) |
HU (1) | HU180786B (fr) |
IE (1) | IE47617B1 (fr) |
IL (1) | IL56219A (fr) |
IT (1) | IT1102753B (fr) |
KE (1) | KE3504A (fr) |
MC (1) | MC1230A1 (fr) |
MY (1) | MY8500248A (fr) |
NL (1) | NL7812312A (fr) |
NO (1) | NO146322C (fr) |
NZ (1) | NZ189203A (fr) |
PT (1) | PT68965A (fr) |
SE (1) | SE7813212L (fr) |
SG (1) | SG5485G (fr) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI67386C (fi) * | 1979-06-21 | 1985-03-11 | Hoffmann La Roche | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara sockerderivat |
EP0084667B1 (fr) * | 1982-01-23 | 1985-09-18 | BASF Aktiengesellschaft | Dérivés de phényléthylène, leur préparation et utilisation à titre de médicaments |
US4588750A (en) * | 1982-07-02 | 1986-05-13 | Hoffmann-La Roche Inc. | Therapeutic compositions for reducing sebum secretion |
DK158947C (da) * | 1982-07-06 | 1991-01-21 | Hoffmann La Roche | Tetrahydronaphthalin-,benzofuran- og benzothiophenderivater, fremstilling og anvendelse deraf samt rodenticid indeholdende saadanne derivater |
US4808597A (en) * | 1983-07-05 | 1989-02-28 | Pfizer Inc. | Method for inhibiting the degradation of cartilage |
EP0155940A1 (fr) * | 1983-08-08 | 1985-10-02 | Sri International | Analogues des acides benzonorbornenyle, benzopyranyle et benzothiopyranyle retinoiques |
FR2555571B1 (fr) * | 1983-11-28 | 1986-11-28 | Interna Rech Dermatolo Centre | Derives du naphtalene, leur procede de preparation et leur application dans le domaine therapeutique |
FR2562539B1 (fr) * | 1984-04-06 | 1987-04-17 | Chauvin Blache Lab | Nouveaux derives de l'acide vinyl-4 benzoique, leur procede de preparation et leurs applications en therapeutique et comme ligands |
EP0170105B1 (fr) * | 1984-07-07 | 1990-10-17 | Koichi Prof. Dr. Shudo | Dérivés de l'acide benzoique |
JPS6122046A (ja) * | 1984-07-07 | 1986-01-30 | Koichi Shiyudo | スチルベン誘導体 |
DE3434944A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | L-substituierte tetralinderivate, ihre herstellung und verwendung |
DE3434942A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Tetralin-derivate, ihre herstellung und verwendung |
DE3434948A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Vinyltetrazolylphenyl-derivate, ihre herstellung und verwendung |
DE3434946A1 (de) | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Diarylacetylene, ihre herstellung und verwendung |
DE3438386A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Phosphorsaeurevinylbenzylester, ihre herstellung und verwendung |
LU85558A1 (fr) * | 1984-09-28 | 1986-04-03 | Oreal | Nouveaux derives naphtaleniques a action retinoique,leurs procedes de preparation et compositions medicamenteuse et cosmetique les contenant |
LU85726A1 (fr) * | 1985-01-10 | 1986-08-04 | Cird | Nouveaux derives naphtaleniques du benzonorbornene,leur procede de preparation et compositions medicamenteuse et cosmetique les contenant |
CA1268125A (fr) * | 1985-06-28 | 1990-04-24 | F. Hoffmann-La Roche Ag | Utilisation d'un retinoide |
ZW7487A1 (en) * | 1986-05-23 | 1987-12-16 | Hoffmann La Roche | Tetrahydronaphthaline and indane derivatives |
US4885282A (en) * | 1987-07-02 | 1989-12-05 | Thornfeldt Carl R | Treatment of hyperhidrosis, ichthyosis and wrinkling |
DE3726806A1 (de) * | 1987-08-12 | 1989-02-23 | Basf Ag | Arylphosphorderivate, ihre herstellung und verwendung |
CA1298309C (fr) * | 1987-11-06 | 1992-03-31 | Michael Klaus | Derives du benzocyclooctene |
US5250562A (en) * | 1988-02-24 | 1993-10-05 | Hoffmann-La Roche Inc. | Stilbene derivatives |
AU618590B2 (en) * | 1988-04-11 | 1992-01-02 | Allergan, Inc. | Tetralin esters of phenols or benzoic acids having retinoid like activity |
DE3903993A1 (de) * | 1989-02-10 | 1990-08-16 | Basf Ag | Diarylsubstituierte heterocyclische verbindungen, ihre herstellung und arzneimittel daraus |
US5196532A (en) * | 1989-02-08 | 1993-03-23 | Basf Aktiengesellschaft | Diaryl-substituted heterocyclic compounds, their preparation and drugs and cosmetics obtained therefrom |
DE3903989A1 (de) * | 1989-02-10 | 1990-09-20 | Basf Ag | Diphenylheteroalkylderivate, ihre herstellung und daraus hergestellte arzneimittel und kosmetika |
DE3926148A1 (de) * | 1989-08-08 | 1991-02-28 | Basf Ag | Diarylacetylene, ihre herstellung und verwendung |
JPH0579665U (ja) * | 1992-03-27 | 1993-10-29 | 株式会社のもと | 読取補助シート |
CA2129773C (fr) * | 1993-09-02 | 2007-05-01 | Michael Klaus | Derives d'acides carboxyliques aromatiques |
FR2743560B1 (fr) * | 1996-01-17 | 1998-04-03 | Europ De Bioprospective Centre | Derives polycycliques aromatiques de type retinoide, leur procede de preparation et leur utilisation pour la fabrication de compositions pharmaceutiques et cosmetiques |
US7226951B2 (en) * | 2003-12-17 | 2007-06-05 | Allergan, Inc. | Compounds having selective cytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitory activity and methods of obtaining the same |
CA2972344C (fr) * | 2007-01-15 | 2021-10-26 | Chongxi Yu | Promedicaments positivement charges solubles dans l'eau de retinoides et de composes semblables a des retinoides ayant des vitesses de penetration dans la peau tres elevees |
US20190112272A1 (en) * | 2016-04-07 | 2019-04-18 | High Force Research Limited | Synthetic retinoids for use in rar mediated conditions |
CN115667190A (zh) * | 2020-06-17 | 2023-01-31 | 贝达药业股份有限公司 | 双环类化合物及其应用 |
-
1978
- 1978-11-29 DK DK536178A patent/DK159967C/da not_active IP Right Cessation
- 1978-12-08 CA CA317,610A patent/CA1123839A/fr not_active Expired
- 1978-12-14 IE IE2472/78A patent/IE47617B1/en not_active IP Right Cessation
- 1978-12-15 DE DE7878101700T patent/DE2861748D1/de not_active Expired
- 1978-12-15 IL IL56219A patent/IL56219A/en not_active IP Right Cessation
- 1978-12-15 FI FI783863A patent/FI68804C/fi not_active IP Right Cessation
- 1978-12-15 EP EP78101700A patent/EP0002742B1/fr not_active Expired
- 1978-12-15 DE DE19782854354 patent/DE2854354A1/de not_active Withdrawn
- 1978-12-18 NZ NZ189203A patent/NZ189203A/en unknown
- 1978-12-19 NL NL7812312A patent/NL7812312A/xx not_active Application Discontinuation
- 1978-12-19 MC MC781349A patent/MC1230A1/fr unknown
- 1978-12-19 FR FR7835651A patent/FR2422620A1/fr active Granted
- 1978-12-20 GR GR27943A patent/GR71656B/el unknown
- 1978-12-20 CS CS788627A patent/CS208158B2/cs unknown
- 1978-12-20 HU HU78HO2122A patent/HU180786B/hu not_active IP Right Cessation
- 1978-12-21 JP JP15699278A patent/JPS54109955A/ja active Granted
- 1978-12-21 NO NO784329A patent/NO146322C/no unknown
- 1978-12-21 AR AR274941A patent/AR224357A1/es active
- 1978-12-21 GB GB7849418A patent/GB2010836B/en not_active Expired
- 1978-12-21 PT PT68965A patent/PT68965A/pt unknown
- 1978-12-21 CY CY1277A patent/CY1277A/xx unknown
- 1978-12-21 AT AT917578A patent/AT361459B/de not_active IP Right Cessation
- 1978-12-21 SE SE7813212A patent/SE7813212L/xx not_active Application Discontinuation
- 1978-12-21 ES ES476224A patent/ES476224A1/es not_active Expired
- 1978-12-22 BR BR7808470A patent/BR7808470A/pt unknown
- 1978-12-22 AU AU42861/78A patent/AU525419B2/en not_active Ceased
- 1978-12-22 IT IT7831277A patent/IT1102753B/it active
- 1978-12-22 DO DO1978002760A patent/DOP1978002760A/es unknown
- 1978-12-25 CU CU7835002A patent/CU35002A/es unknown
-
1985
- 1985-01-22 SG SG54/85A patent/SG5485G/en unknown
- 1985-02-18 KE KE3504A patent/KE3504A/xx unknown
- 1985-04-18 HK HK301/85A patent/HK30185A/xx unknown
- 1985-12-30 MY MY248/85A patent/MY8500248A/xx unknown
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